Inspections, Compliance, Enforcement, and Criminal Investigations

Merrill D. Benson, M.D. 3/20/17

 

  

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10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

WARNING LETTER
 
 
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
 
 
Merrill D. Benson, M.D.                                                                       Ref.: 17-HFD-45-03-01
Indiana University
School of Medicine
Department of Pathology
635 Barnhill Drive, MS-128
Indianapolis, Indiana  46202-5126
 
Dear Dr. Benson:
 
This Warning Letter informs you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at your clinical site between October 11, 2016, and November 10, 2016. Ms. Myra K. Casey, Mr. Lewis K. Antwi, and Ms. Melanie N. Daniels, representing FDA, reviewed your conduct of a clinical investigation (Protocol (b)(4)) of the investigational drug (b)(4), which you performed as a sponsor-investigator.
 
This inspection is a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of FDA-regulated research to ensure that the data are scientifically valid and accurate, and to help ensure that the rights, safety, and welfare of the human subjects in the studies are protected.
 
At the conclusion of the inspection, Ms. Casey and Mr. Antwi presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your November 30, 2016, written response to the Form FDA 483. 
 
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated November 30, 2016, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:
 
You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].
 
As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) specifies requirements for safety monitoring, defines protocol-specific stopping rules, and requires you to perform certain study procedures at specific times, such as platelet count measurements, clinical chemistry panel tests, and urinalysis laboratory tests. In addition, the investigational plan for Protocol (b)(4) requires you not to enroll subjects who meet the exclusion criteria.  You failed to adhere to these requirements. Specifically: 
 
1.    The investigational plan for the above-mentioned protocol requires that platelets be monitored approximately every week for the duration of the study; and if for any reason 14 days has elapsed since the last available platelet value, dosing must be held until a platelet count is obtained and reviewed by the investigator. Of note, in a separate randomized controlled study, three subjects given the study drug (b)(4) or placebo had temporary decreases in their platelet counts; however, it is not known if these decreases were related to the study drug. Therefore, frequent monitoring of platelet counts and strict adherence to protocol-specific stopping rules are important to protect the rights, safety, and welfare of study subjects.
 
a.  For Subject CM 01, weekly platelet measurements were not performed between May 23, 2016, and June 12, 2016. During this time frame, more than 14 days elapsed without platelet testing; however, the study drug was not held.
 
b.  For Subject CM 17, weekly platelet measurements were not performed between May 24, 2016, and June 14, 2016. During this time frame, more than 14 days elapsed without platelet testing; however, the study drug was not held.
 
In your November 30, 2016, written response to the Form FDA 483, you agreed with the observations that platelets were not drawn during the specified time frames. You noted that in light of the reports concerning life-threatening thrombocytopenia in subjects treated with (b)(4), monitoring of subjects’ platelets is of the utmost importance. You indicated that the study team will track scheduled dosing dates and all platelet count results for each subject, ensuring that each subject has a platelet level that has been reviewed and is acceptable on the day before each scheduled dosing. You also noted that if either of these factors is not met, the subject will be informed to hold their scheduled dosing until the clinical investigator has received a platelet count result and confirms that it is acceptable under the guidelines in the protocol.
 
We are unable to determine if your written response provides a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details about your plan for implementing additional measures and procedures to address the inspection findings concerning your failure to follow protocol procedures. For example, you did not indicate whether you and your staff underwent retraining activities to prevent future protocol violations. In addition, your written response does not provide sufficient details about how you personally will ensure adequate oversight of study procedures (for example, protocol-required safety monitoring and stopping rules) and good clinical practice training for you and your study staff. Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future. 
 
As mentioned above, frequent monitoring of platelets and strict adherence to protocol-specific stopping rules are essential to protect the rights, safety, and welfare of subjects participating in the study. Failure to adhere to protocol-required safety monitoring and stopping rules, particularly those related to platelet count results, jeopardizes subject safety and welfare. 
 
2.      The investigational plan required you to exclude subjects with renal insufficiency, defined as any subject with an estimated creatinine clearance (Cockroft-Gault formula) for 24-hour urine creatinine clearance <35 mL/min/1.73 m2 at screening. 
 
You enrolled Subject CM 04 into Protocol (b)(4) on December 19, 2014, even though this subject had a known history of renal insufficiency and an estimated creatinine clearance (Cockroft-Gault formula) of 27 mL/min/1.73 m2 at screening.
 
In your November 30, 2016, written response to the Form FDA 483, you acknowledged that this subject’s 24-hour urine creatinine clearance did not meet the eligibility requirements, and that enrollment of this subject was a protocol deviation. You also indicated that you made an exception to this exclusion criterion and enrolled this subject because, as you noted, you were aware that the subject was followed by a nephrologist for renal insufficiency, likely related to arteriolar nephrosclerosis; and that laboratory tests indicated that the subject’s renal function had been stable for more than one year before the subject entered the study.
 
We are unable to determine if your written response provides a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details about your plan for implementing additional measures and procedures to address the inspection findings regarding the enrollment of ineligible subjects. For example, you did not indicate whether you and your staff underwent retraining activities to prevent future protocol violations. In addition, your written response does not provide sufficient details about how you personally will ensure adequate oversight of study procedures (for example, adherence to eligibility requirements) and protocol training for you and your study staff. Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future. 
 
We emphasize that the eligibility criteria for each clinical investigation are designed both to optimize interpretability of collected data, and to minimize foreseeable harm to enrolled subjects. Enrollment of subjects who do not meet the eligibility criteria jeopardizes subject safety and welfare, and raises concerns about the validity and integrity of the data collected at your site.
 
3.      The investigational plan requires that you perform clinical chemistry panels and urinalysis laboratory tests at Screening and at Weeks 1, 6, 13, 26, 39, 52, 78, 104, and 117. For Protocol (b)(4), clinical chemistry panels include measurement of magnesium, phosphorus, and uric acid.  You failed to conduct the following clinical laboratory tests at the specified intervals:
 
 

      Subject ID
      Laboratory tests not performed
      Study week(s) when these
      tests were not performed
      CM 02
      Magnesium and phosphorus
6
      Uric acid
52 and 78
      CM 07
      Urinalysis 
78
      CM 10
      Urinalysis
6, 13, and 26
      CM 11
      Magnesium and phosphorus
Screening
      Uric acid
13 and 26
      CM 18
      Magnesium and phosphorus
1
      Uric acid
1 and 6

 
 
We acknowledge that the findings in Item 3. above for Subject CM 11’s Week 13 uric acid laboratory test, and for Subject CM 18’s Week 1 uric acid laboratory test, were not included on the Form FDA 483 you received; and that therefore, your written response does not address this finding.
 
In your November 30, 2016, written response to the Form FDA 483, you acknowledged that certain urinalysis and laboratory tests for magnesium, uric acid, and phosphorus  were not performed for these subjects. You noted that these deficiencies demonstrate a need to train your clinical research team, to ensure that all subjects have the required tests performed according to the protocol. As part of your corrective action plan, you indicated that when a laboratory test is missed, a member of your clinical research team will request that laboratory test to be performed and will obtain the result of that laboratory test.  You also indicated that you acquired an independent monitor to monitor your clinical research team’s adherence to the protocol requirements for laboratory testing. 
 
We are unable to determine if your written response provides a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details about your plan for implementing additional measures and procedures to address the inspection findings concerning your failure to follow protocol procedures. For example, you did not indicate whether you and your staff underwent retraining activities to prevent future protocol violations. In addition, your written response does not provide sufficient details about how you personally will ensure adequate oversight of study procedures (for example, completion of protocol-required tests at specified intervals) and protocol training for you and your study staff. Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future. 
 
Failure to perform protocol-required procedures, including clinical laboratory tests used to monitor subject safety and tolerability, jeopardizes subject safety and welfare, and raises concerns about the validity and reliability of the data collected at your site. 
 
This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address these deficiencies and establish procedures to ensure that any ongoing or future studies will be in compliance with FDA regulations.
 
Within fifteen (15) working days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address the violations noted above adequately and promptly may result in regulatory action without further notice. If you believe you have complied with FDA regulations, include your reasoning and any supporting information for our consideration. 
 
If you have any questions, please contact Adam Donat, M.S., at 301-796-5316; FAX 301-847-8748.  Your written response and any pertinent documentation should be addressed to:
 
Adam Donat, M.S.
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Postmarketing Safety
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Building 51, Room 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993
                                                                
Sincerely yours,
 
{See appended electronic signature page}
 
David C. Burrow, Pharm.D., J.D.
Acting Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
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DAVID C BURROW
03/20/2017

Page Last Updated: 05/08/2017
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